Adverse effects of cannabis

Prior to the 1980s, cannabis was not thought to produce significant dependence [6]. Physical dependence, particularly the presence of a withdrawal syndrome, was not well characterized, animal models had not convincingly demonstrated reinforcing effects, and the neurobiology of cannabis was not well understood. Further, cannabis use did not appear to cause the dramatic harms typified by other drugs of abuse, such as alcohol, cocaine, and heroin. Discussion of adverse effects often focused on the “amotivational” syndrome [7], a syndrome that was never fully disentangled from cannabis intoxication itself.

Cannabis receptors

The primary psychoactive component of cannabis, tetrahydrocannabinol (THC), was identified in 1965 [8], but it was not until the 1990s, when the first cannabinoid receptor (CB1) was described, that researchers began to characterize the endocannabinoid system [9]. CB1 receptors were found to be localized throughout the brain, and while their purpose was not well-understood, cannabis exposure was shown to alter them [10]. The development of cannabinoid receptor antagonists permitted studies of precipitated withdrawal, which added to the mounting evidence of a clinically significant and specific cannabis withdrawal syndrome [11]. Cannabis was also shown to promote release of dopamine in the nucleus accumbens, one of the cornerstone features of reinforcing drugs [12].

Broadening of addiction concept

Simultaneously, in the late 1970s and early 1980s, the conceptualization of addiction began to change. Rather than focusing on physical dependence, the phenomenology of addiction broadened to include such constructs as compulsivity, loss of control, consequences, salience, and relapse [13]. DSMIII codified a view of substance dependence for which symptoms of physical dependence were neither necessary nor sufficient for establishing a diagnosis [14]. Among regular cannabis users, a dependence syndrome very similar to that described for other drugs of abuse was reliably described [15]. Users described unsuccessful attempts to cut down, use despite knowledge of persistent psychological or physical problems, excessive time spent buying, using or recovering from cannabis effects, and loss of control over use [16]. Perhaps the most important factor demonstrating the validity and clinical significance of cannabis dependence was that many heavy users sought help with problems related to cannabis use. Cannabis was the most common illicit drug responsible for substance abuse treatment admissions in the US in 2007, and among youth under the age of 19, primary cannabis abuse accounted for over half of all admissions [17].

Adverse effects of cannabis

Epidemiological surveys revealed subtle but significant adverse outcomes associated with cannabis dependence. Chronic heavy use was associated with poor educational attainment among youth [18], an unsurprising association given the fact that cannabis intoxication directly impairs cognition, and some studies [19–21], but not all [22, 23], pointed to subtle but persistent long term impairments. Cannabis use during adolescence may be distinct in that, alongside the putative neurobiological consequences of heavy cannabinoid exposure [24], chronic intoxication may fundamentally alter developmental trajectories [25, 26]. Heavy cannabis use has been linked to school failure, early pregnancy, crime, and progression to further drug use [18, 27, 28]. Even where these associations are demonstrated in prospective, longitudinal studies that control for baseline (i.e., pre-cannabis use) presence of the adverse outcome and known common risk factors (e.g., other substance use, psychiatric co-morbidity), it remains possible that the observed associations result from convergent risks and common predisposing factors, as much as direct effects of cannabis use.

Cannabis dependence and other disorders

With regards to mental health, individuals with cannabis dependence were found to be six-fold more likely to have mood or anxiety disorders [29], and cannabis use was repeatedly correlated with poor clinical outcomes and exacerbation of symptoms across many psychiatric disorders [30–33]. A causal relationship between cannabis use and affective disorders has not been established. However the link between cannabis use and risk of psychotic disorders has now been replicated across at least six well-controlled prospective longitudinal studies [34], and specific genetic factors are emerging as plausible explanations for increased risk among subsets of users [30, 35, 36]. Demonstrating causality with epidemiological or association studies is impossible because of the inability to ever completely exclude the presence of unmeasured shared predisposing or risk factors (common antecedent causality) or subtle presence of the adverse outcome at baseline (reverse causality) [37, 38], but the consistency of the associations described above has fundamentally changed the appraisal of “hazard” associated with heavy cannabis use.

Cannabis dependence poses some distinct challenges for treatment providers. The evolving sociocultural context of use for medical (as opposed to recreational) purposes, policy liberalization, and societal normalization has contributed to decreased perceived risk and increased acceptability of use [39–43]. Simultaneously, the comparatively lower “severity” of cannabis-associated consequences (compared with other drugs of abuse) [44] makes it more difficult for some users to recognize the impact of their use and establish an enduring commitment to change. As a result, many treatment seekers are reluctant to accept traditional abstinence-based goals [45]. Among treatment providers, consensus has not been established about the value of non-abstinence goals, such as moderation and harm reduction.

Cannabis withdrawal

Most symptoms begin during the first week of abstinence and resolve after a few weeks. Up to one-half of patients in treatment for cannabis use disorders report symptoms of a withdrawal syndrome [11, 48–50]. Although not medically serious, cannabis withdrawal should be a focus of treatment, because it may serve as negative reinforcement for relapse to cannabis use in individuals trying to abstain [48, 51].

Cannabis dependence

No medication has been shown broadly effective in the treatment of cannabis dependence, nor is any medication approved for this condition by any regulatory authority. Ongoing research is evaluating 3 major strategies for treatment: agonist substitution, antagonist, and modulation of other neurotransmitter systems.

Motivational Enhancement Therapy (MET)

MET is a patient-centered therapy that seeks to help individuals resolve ambivalence in order to generate commitment to change [85]. MET views readiness to change as a dynamic process involving multiple stages: pre-contemplation, contemplation, preparation, action, and maintenance (consider using a figure to demonstrate these), and proposes that the role of the therapist is to create the conditions that promote the patient’s intrinsic motivation [86]. Five core tenets characterize the motivational “style:” [87].

1. Maintain empathy and create a respectful, non-judgmental therapeutic frame through the use of open ended questions and validation
2. Develop cognitive discrepancy by identifying goals that are meaningful to the patient and incrementally linking them to contrary behaviors
3. Avoid arguments that cause patients to become defensive by letting the patient lead and working from within their perspective
4. Roll with resistance by using reflective interpretations and re-framing rather than confrontations
5. Support self-efficacy to engender confidence in the ability to make and sustain change by utilizing support and validation

Whereas in clinical practice, MET may be used repeatedly over time as the targets for behavioral change evolve, in clinical studies, MET sessions are typically 60 to 90 minutes long, with treatment occurring over one to four sessions. MET has been shown to improve cannabis related outcomes among treatment-seeking adults [88], non-treatment seekers [89], and individuals with co-occurring disorders [90]. There have been efforts to computerize motivational interventions [91, 92], simplify them for use in community settings and busy primary practices, and utilize them in inpatient settings for patients with significant co-occurring disorders [93]. Studies of brief motivational interventions in adolescents show only minimal impact on cannabis use outcomes [94, 95] However, these studies have reinforced the feasibility of brief motivational interventions for moderating use and improving education [96]. It remains to be seen whether brief interventions for non-treatment seeking cannabis users will increase the possibility of self-directed change by facilitating openness to education and consideration of future intervention [94].

Cognitive Behavioral Therapy (CBT)

Cognitive behavioral therapy views drug use as a learned behavior. CBT posits that by identifying the associative links and chain of events precipitating use, patients can identify opportunities to alter their behavioral repertoire and use alternative, healthy coping mechanisms [97]. CBT begins by establishing a therapeutic framework and teaching self-monitoring of underlying triggers. The therapy then moves to the development of relapse prevention skills, such as relaxation techniques, mindfulness, cognitive re-structuring, positive self-talk, and assertiveness. The therapist may impart these skills through instruction, modeling and role playing, but eventually the patient is encouraged to practice those skills outside of therapy, such that they develop the skills to adaptively deal with high-risk situations without relapsing.

CBT is typically provided over 6 to 12 individual or group sessions. The earliest randomized psychotherapy studies for cannabis dependence showed small but significant benefits [98, 99]. CBT was not superior to MET [49], but the synergies offered compelling rationale to integrate them [100]. Subsequent studies have demonstrated efficacy for CBT in the context of brief interventions [98], combination with motivational techniques and contingency management [101, 102], and for individuals with co-occurring disorders [90, 93, 103].

Contingency Management (CM)

Contingency management posits that behaviors will increase or decrease as a function of immediate and directly associated consequences. By manipulating the quality and immediacy of external consequences, contingency management attempts to systematically increase the likelihood of desired behaviors, and minimize undesired behaviors. Studies of CM show that rewards are generally more effective than punishments and that they do not have to be large or monetary to substantially alter behaviors [104]. For goals such as abstinence, that require continuous behavior, escalating values of reward can be very effective (i.e., longer periods of continuous abstinence increase the value of the reinforcer, while relapse resets the reinforcer back to a minimal level) [104, 105]. Rewards are most effective when they are provided in close proximity to the desired behavior, and frequency of reinforcement increases efficacy [105]. Whereas traditionally CM links rewards to abstinence confirmed by urine monitoring, CM can be effectively tied to a broader set of therapeutic goals, including attendance of counseling sessions, completion of therapy-related assignments, and adherence to medications.

The first randomized study of CM for cannabis dependence demonstrated that adding voucher-based incentives could improve responses to a motivational behavioral coping skills intervention [101]. CM is not a replacement for motivational enhancement or skill building, but can be used to augment the decisional balance among patients who would not otherwise be ready to address their substance use. In accordance with this, studies consistently show that, while not effective in isolation, CM reliably augments treatment outcomes of other effective psychotherapies [106, 107]. CM also improves engagement among non-treatment seeking adults with cannabis dependence, such as those referred by probation [108], and young adults referred by the criminal justice system [102]. At least one study showed promise for utilization of CM among adolescents [109], as well as for individuals with severe persistent mental illness [110].

Supportive-Expressive Psychotherapy (SEP)

Supportive-Expressive psychotherapy has many characteristics similar to motivational and skills-based treatment. The supportive element of the therapy involves establishing a helpful, optimistic, encouraging, and empathic relationship between the patient and therapist. The development of a strong therapeutic alliance enables an expressive component, in which the therapist utilizes reflective listening and interpretation to explore the patient’s subjective experience, point out patterns that manifest within the therapeutic relationship, and facilitate development of self-awareness, insight, and adaptive coping [111]. Through self-understanding, SEP aims to help patients achieve greater mastery over problem behavior and improved personal well-being [112].

Supportive-Expressive psychotherapy is typically delivered in hour-long sessions, once or twice each week, over at least 4 months. In contrast to other therapies discussed, SEP has not been studied in well-controlled randomized trials, but is worth mention because it is a commonly utilized technique among community providers of psychotherapy. One poorly controlled study compared a 16-week supportive-expressive intervention to a single session self-help intervention for cannabis dependence—significant abstinence was achieved at the close of therapy, but statistically significant gains were not maintained over the subsequent year [113].

Family and Systems Interventions

Recognizing the complex interplay of psychosocial factors for many cannabis-dependent youth, system based interventions have been established to involve family, utilize case managers to decrease obstacles, incorporate community supports to navigate environmental challenges, and collaborate with other stakeholders such as schools. Three manualized “systems” interventions have been studied among cannabis-using adolescents. Family therapy views the family as the patient, taking a family systems approach to resolving problems, by enhancing intra-family communication, improving parental limit setting, and facilitating collaborative recovery work [114]. The Adolescent Community Reinforcement Approach (ACRA) is a multi-system behavioral therapy that seeks to integrate cognitive behavioral skills training with collaborative community support, and contingency management [115]. Multidimensional family therapy (MDFT) is a comprehensive systems therapy that targets the functioning of the individual within the context of his or her environment by integrating individual therapy, parent coaching, family systems therapy, and engagement of key community stakeholders, such as school, medical supports, juvenile justice, and social services [116].

In small randomized trials, MDFT has shown greater and more sustainable gains than CBT [117], group therapy, and MET interventions alone [118]. However, MDFT was not significantly better when compared with other high quality treatment interventions in the Cannabis Youth Treatment (CYT) study, which randomized 600 adolescents to five different treatment approaches across multiple sites [119, 120]. The treatment interventions included ACRA, Family Support Network, Multidimensional Family therapy, and a five-session and twelve-session version of combined MET and CBT. The CYT study had good retention rates, acceptability of manual-based interventions to therapists, treatment efficacy (across all arms), and economic feasibility (costs were comparable to national outpatient program costs). Long-term follow-up data are anticipated, as are initial findings from a large international study of MDFT, which is currently under way [116].

Dr. Gorelick is supported by the Intramural Research Program, National Institutes of Health, National Institute on Drug Abuse. He has participated in NIH research sponsored by a Collaborative Research and Development Agreement with Sanofi-aventis, the maker of rimonabant.